Incidence of Hereditary Nonpolyposis Colorectal Cancer and the Feasibility of Molecular Screening for the Disease

Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P, Chadwick RB, Kaarianen H, Eskelinen M, Jarvinen H, Me
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2001

Reviewers: Kenneth Blank, MD and John Han-Chih Chang, MD
Source: The New England Journal of Medicine, Volume 338 (21):1481

Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder which, predisposes people to colon and other cancers. This disorder is characterized by mutations to genes in the mismatch repair family. To date, eight members of this 'gene family' have been discovered. All eight of these genes encode proteins that function to repair DNA which, is incorrectly copied, and are appropriately called DNA mismatch repair genes. A mutation to any one of the eight known mismatch repair genes can lead to HNPCC. The two most commonly mutated genes are MSH2 and MLH1, which are mutated in the majority of HNPCC families. Persons who carry mutations to their DNA mismatch repair genes carry an 80% chance of developing colon cancer by 75 years of age.

Unlike other genetic disorders which are easily diagnosed -- for example a patient afflicted with cerebral palsy is readily diagnosed based on clinical features -- the diagnosis ofHNPCC relies on a very strongly positive family history of colon cancer. Specifically, several organizations have defined criteria that must be met to make the diagnosis of HNPCC. The most widely accepted of these are the Amsterdamcriteria, which include:

  1. Three affected relatives
  2. Two generations affected
  3. One relative affected before age 50.
All three criteria must be met to make the diagnosis of HNPCC.

Although HNPCC lacks strict clinical distinctions which can be used to make the diagnosis -- and we therefore rely on the strong family history -- scientists are now able to study patients' DNA for mutationsto one of the mismatch repair genes. A mutation to one of these genes is a characteristic feature and confirms the diagnosis of HNPCC.Identifying individuals with this disease and performing screening colonocsopes on affected persons may help reduce colon cancer mortality.

The problem comes in the question of who to screen? HNPCC is a relatively rare disease which makes screening the entire populace burdensome and not cost-effective Screening patients with colon cancer -- with the hope of helpingtheir relatives -- is a more reasonable approach but even among this select group the incidence of HNPCC may be too small to make screening effective.

The May 21, 1998 New England Journal of Medicine reports a study from Finland in which 509 consecutive patients with colorectal cancer were screened for DNAreplications error -- which is a surrogate marker for a mutation to the mismatch repair genes. Patients who tested positive for replication errors underwent more extensive DNA testing to search for a mutation to either MLH1 or MSH2.

Sixty-three of the 509 patients tested positive for a replication error. Ten of the 63 tested positive for a mutation to either MLH1 or MSH2 (2 percent of the 509). Of these 10, 7 had a family history fulfilling theAmsterdam criteria. These findings led the authors to conclude that patients with colon cancer should be tested for replication errors and those that are positive be tested for mutations to MLH1 or MSH2.Patients who are found to have such mutations and their families should undergo genetic counseling.


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